3-oxo-2(H)-1,2,4-triazine derivatives as ligands of 5 HT1A receptors

ABSTRACT

The invention concerns novel 3-oxo-(2H)-1,2,4-triazine derivatives of general formula (I) in which R 1  represents: hydrogen, when A is an optionally substituted nitrogen atom; a linear or branched  1 -C 4  alkyl group; a C 1 -C 4 phenyl alkyl group, the phenyl ring being optionally substituted by one or several groups such as C 1 -C 4  alkyl, C 1 -C 3  alkoxy, halogen, trifluoromethyl. R 2  represents: hydrogen; a linear or branched C 1 -C 4  alkyl radical; a C 1-C   4  phenyl or phenylalkyl group, the phenyl ring being optionally substituted by one or several groups such as C 1 -C 4  alkyl, C 1 -C 3  alkoxy, halogen, trifluoromethyl. A represents an oxygen atom or a nitrogen atom optionally NR 3  substituted. R 3  represents hydrogen or a methyl group. B represents a group such as (IIa) in which Ar itself represents an aromatic structure such as phenyl, pyridyl or pyrimidyl, optionally substituted by one or several groups such as C 1 -C 3  alkyl, C 1 -C 3  alkoxy, hydroxy, trifluoromethyl or halogen and n can be whole numbers ranging between 3 and 5; (IIb) in which Ar is as defined in formula (IIa) and m can be a whole number ranging between 1 and 2; (IIc) in which R 4  represents hydrogen or a C 1 -C 3  alkyl group and n can be whole numbers ranging between 3 and 5.

This is a 371 filing of PCT/FR98/02205 filed Oct. 14, 1998.

A subject-matter of the present invention is novel 3-oxo-(2H)-1,2,4-triazine derivatives functionalized in the 5 position, theirpreparation and their application in therapeutics.

5-HT_(1A) receptors have been claimed for their role in variouspathologies, such as hypertension, sexual dysfunctioning, anorexia ormemory. The main target suggesting the involvement of the 5-HT_(1A)receptors is, however, composed of disorders of the central nervoussystem, such as anxiety and depression. The hypotheses, supported bytests on animal models and clinical studies, suggest that more effectivetreatments of these pathologies can be envisaged with 5-HT_(1A) agonistcompounds with a high affinity which are very selective and highlyeffective.

3,5-Dioxo-(2H,4H)-1,2,4-triazine derivatives and3,5-dioxo-6-amino-(2H,4H)-1,2,4-triazine derivatives have been claimedpreviously by the Applicant Company (FR 2,707,294 of Jun. 7, 1993 and FR2,727,682 of Feb. 12, 1994).

The compounds of the present invention are characterized by theirpowerful affinity with regard to the 5-HT_(1A) receptor in combinationwith a high selectivity, in particular with regard to D₂ and α₁receptors, and a high intrinsic activity.

The compounds of the invention correspond to the general formula I

in which

R₁ represents:

hydrogen, when A is an optionally substituted nitrogen atom

a linear or branched C₁-C₄ alkyl group

a C₁-C₄ phenylalkyl group, the phenyl nucleus optionally beingsubstituted by one or more groups, such as C₁-C₄ alkyl, C₁-C₃ alkoxy,halogen or trifluoromethyl,

R₂ represents:

hydrogen

a linear or branched C₁-C₄ alkyl radical

a C₁-C₄ phenyl or phenylalkyl group, the phenyl nucleus optionally beingsubstituted by one or more groups, such as C₁-C₄ alkyl, C₁-C₃ alkoxy,halogen or trifluoromethyl,

A represents an oxygen atom or an optionally substituted nitrogen atomNR₃,

R₃ represents hydrogen or a methyl group,

B represents a group of type

 in which Ar itself represents an aromatic structure, such as phenyl,pyridyl or pyrimidyl, optionally substituted by one or more groups, suchas C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl, trifluoromethyl or halogen, andn can take the integral values from 3 to 5,

 in which Ar is as defined in the formula IIa and m can take theintegral values 1 and 2,

 in which R4 represents hydrogen or a C₁-C₃ alkyl group and n can takethe integral values from 3 to 5.

The invention covers the inorganic or organic salts of compounds ofgeneral formula I with pharmaceutically acceptable acids.

In addition, it covers the various enantiomers and diastereoisomers ofthe compounds which have one or more asymmetric carbons, as well astheir mixtures in all proportions, including in particular the racemicmixtures.

Synthesis

The compounds of the present invention can be prepared according tovarious methods. They can be synthesized by using the synthetic routesdescribed hereinbelow or by using synthetic methods known to a personskilled in the art.

The synthesis of the compounds of general formula I is characterized inthat a derivative of general formula III (Scheme 1)

is condensed with an alcohol B-OH IV or an amine BHNR₃ V, R₁, R₂, R₃ andB having the same meaning as above in the general formula I.

The compounds III are obtained according to a process (Scheme 1)characterized by the following stages:

1—Condensation of glyoxylic acid with thiosemicarbazide, followed by abasic treatment, such as sodium hydroxide solution,

2—Methylation by methyl iodide in basic aqueous medium, followed by anacidic treatment, such as hydrochloric acid,

3—Sulfuration of the 5 position in the presence of Lawesson's reagent ina solvent such as pyridine,

4—Methylation by methyl iodide in basic aqueous medium, such as sodiumhydroxide solution,

5—Alkylation of the 2 position by an alkyl halide R₁X in the presence ofNaH in DMF, X representing C1, Br or

Synthesis of the Compounds III (Scheme 1)

The condensation of intermediates III with the alcohols IV or amines Vis carried out in the presence of a base, such as sodium hydride orpotassium tert-butoxide in dioxane, THF or toluene.

The optional separation of the enantiomers or diastereoisomers ofcompounds having one or more asymmetric carbons is generally carried outon the final products by liquid chromatography on a chiral column.

Synthesis of the Alcohols B-OH IV

A—When B represents a group of type

the corresponding alcohols

can be obtained

1) by treating the piperazine

 with a haloalcohol

HO—(CH₂)_(n)—Hal  VII

 in the presence of K₂CO₃ and optionally of KI, when Hal=Br or Cl, inacetonitrile at reflux,

2) when n=4 or 5, by treating the piperazine VI with a lactone VIII

 in the presence of a Lewis acid, such as AlCl₃, and of triethylamine indichloromethane, and by then reducing the amide IX formed

 with a hydride, such as LiAlH₄ in THF,

3) when Ar represents a heterocycle of pyrimidine type, by treatingoptionally substituted 2-chloropyrimidine with a hydroxyalkylpiperazineX

 bin a solvent, such as toluene, in the presence of an amine, such astriethylamine.

B—When B represents a group of type

1) when m=1,

according to the process disclosed in the Pfizer Patent WO 93 25552(1992),

2) when m=2, by oxidizing the alcohol XI

 under the Swern conditions and by then treating the aldehyde obtainedXII

 with a Wittig reagent, such as methoxymethyltriphenylphosphoniumchloride in TrHF, followed by the hydrolysis in aqueous acidic medium ofthe enol ether obtained XIII

 to result in the corresponding aldehyde XIV

 which is reduced to the alcohol with a hydride, such as NaBH₄ inethanol.

C—W hen B represents a group of type

the corresponding alcohols

can be prepared

1) by treating benzodioxanemethylamine according to the processdescribed in paragraph A-2,

2) by condensing benzodioxanemethanol with an aminoalcohol XV

HO—(CH₂)_(n)—NH₂  XV

Synthesis of the Amines B-NHR₃ V

1) When R₃=H,

the compounds V are commercial amines or can be obtained conventionally,such as generation of the primary amine from the intermediatephthalimide.

2) When R₃=Me,

the compounds are obtained from the amines BNH₂ (the method ofpreparation of which is described hereinabove) by formylating the aminewith formic anhydride in a solvent, such as pyridine, to result in theformamide XVI

which is reduced with a hydride, such as LiAlH₄ in THF.

The following examples illustrate the invention without limiting thescope thereof.

The elemental analyzes and the IR and NMR spectra confirm the structuresof the compounds obtained according to the invention.

EXAMPLE 12-Methyl-5-[4-(4-pyrimidin-2-yl-piperazin-l-yl)Butoxyl-2H-[1,2,4]Triazin-3-One(1)

a) 5-Thioxo-4,5-dihydro-2H-[1,2,4]triazin-3-one (1a)

98.3 g (243 mnol) of Lawesson's reagent are added to a solution of2H-[1,2,4]triazin-3,5-dione (50 g, 442 mmol) in 400 ml of pyridine. Themixture is brought to reflux for 4 h. After evaporating the solventunder reduced pressure, the residue obtained is taken up in 400 ml ofwater. The brown precipitate which forms is isolated by filtration.These crystals are taken up in H₂O and extracted with ethyl acetate.After drying the organic phases (MgSO₄) and concentrating them todryness, yellow crystals are obtained.

Retreatment of the aqueous solution (400 ml) by extracting with ethylacetate makes it possible to isolate a further solid fraction. In total,after drying, 60 g of yellow crystals are obtained.

M.p.=239° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.4.

b) 5-Methylsulfanyl-2H-[1,2,4]triazin-3-one (1b)

The compound 1a (30 g, 232 mmol) and CH₃I (15.9 ml, 255 mmol) are placedin 300 ml of water. 18.6 g of NaOH (465 mmol) are added and the mixtureis stirred for 1 h at room temperature. The reaction mixture, cooled ona bed of ice, is neutralized using 27 ml of acetic acid and thenextracted with dichloromethane. The organic phases are dried (MgSO₄) andthen concentrated to dryness. After recrystallizing from ether, 29.9 gof compound 1b are isolated.

M.p.=171° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.5.

c) 2-Methyl-5-methylsulfanyl-2H-[1,2,4]triazin-3-one (1c)

A suspension, placed under nitrogen, of NaH (60% in liquid paraffin, 4.4g, 110 mmol) in 50 ml of DMF is cooled to 0° C. on a bed of ice. Thecompound 1b (15.9 g, 111 mmol), diluted in 100 ml of DMF, is run intothis suspension dropwise. The mixture is subsequently stirred for 1 h atroom temperature.

After concentrating the reaction mixture to dryness, the residue istaken up in H₂O and extracted with CH₂Cl₂. The organic phases are driedover MgSO₄ and then evaporated under reduced pressure.

After crystallizing from EtOH/isopropyl ether and then drying, 13.9 g ofproduct 1c are isolated in the form of beige crystals.

M.p.=106° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 95/5,Rf=0.52.

d) 4-Hydroxy-1-(4-pyrimidin-2-yl-piperazin-1-yl)butan-1-one (1d)

AlC₃ (18.5 g, 138.8 mmol) is suspended in 100 ml of dichloromethaneunder an inert atmosphere (N₂). A solution of triethylamine (22.3 ml,160 mmol) diluted in 40 ml of dichloroethane is run dropwise onto thismixture cooled to 0° C. on a bed of ice.

This mixture is brought back to room temperature and then a solution of2-pyrimidinylpiperazine (19.5 g, 119 mmol) and butyrolactone (8.2 ml,107 mmol) in 80 ml of dichloroethane is added dropwise.

This mixture is stirred for 2 h at room temperature and then pouredquickly onto 200 ml of ice. After extracting with dichloromethane,drying the organic phases (MgSO₄) and concentrating them to dryness, 27g of crystals are recovered and are used in the following stage withoutadditional purification.

e) 4-4-Pyrimidin-2-yl-piperazin-1-yl)butan-1-ol (1e)

LiAlH₄ (4.9 g, 129 mmol) is suspended in 100 ml of THF under nitrogen.1d (27 g, 108 mmol), diluted in 150 ml of THF, is added dropwise whiletaking care to maintain the temperature at room temperature. Thismixture is stirred for 1 h, hydrolyzed with the minimum amount of waterand dried over MgSO₄. After filtering off the aluminum salts, thefiltrate is concentrated to dryness. The residue obtained is purified bysilica flash chromatography (eluent: CH₂Cl₂/MeOH: 95/5).

17.3 g of yellow oil are recovered. After salifying with fumaric acid inethanol, a white solid is isolated.

M.p.=112° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄OH: 90/9/1,Rf=0.54.

f)2-Methyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butoxy]-2H-[1,2,4]triazin-3-one(1)

NaH (60% in liquid paraffin, 0.68 g, 17 mmol) is placed indimethoxyethane (DME) under an inert atmosphere. A solution of compound1e (in the base form, 4.5 g, 19 mmol) diluted in 20 ml of DME is addeddropwise to this mixture cooled to 0° C.

The reaction mixture is stirred for 1 h at room temperature and thenbrought back to 0° C. A solution of 1c (3 g, 19.1 mmol) diluted in 40 mlof DME is then run n dropwise. The temperature of the reaction mixtureis subsequently brought back to room temperature and stirring ismaintained for 1 h.

The inorganic products are filtered off under vacuum and the filtrate isconcentrated to dryness. The residue obtained is purified by silicaflash chromatography (eluent: CH₂Cl₂/MeOH: 95/5), which makes itpossible to isolate a yellow oil which crystallizes.

After recrystallizing from acetone, 2 g of compound 1 are obtained.

M.p.=134° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.46.

EXAMPLE 22-Methyl-5-[4-[4-(4-methylpyrimidin-2-yl)piperazin-1-yl]butoxyl]-2H-[1,2,4]triazin-3-onefumarate (2)

a) 4-[4-(4-Methylpyrimidin-2-yl)piperazin-1-yl]butan-1-ol (2a)

4-Methyl-2-piperazin-1-yl-pyrimidine dihydrochloride (7 g, 38.8 mmol)and 4-chlorobutanol (4.6 ml, 46 mmol) are placed in 150 ml ofacetonitrile in the presence of K₂CO₃ (21.5 g, 155.5 mmol). This mixtureis brought to reflux for 16 h. After cooling, the inorganic products areremoved by filtration and the filtrate is concentrated to dryness.

The residue obtained is purified by silica flash chromatography (eluent:CH₂Cl₂/MeOH: 90/10). 4.7 g of white crystals are obtained.

M.p.=76° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.41.

b)2-Methyl-5-[4-[4-(4-methylpyrimidin-2-yl)piperazin-1-yl]butoxy]-2H-[1,2,4]triazin-3-onefumarate (2)

This compound is prepared according to the process described in Stage fof Example 1 using4-[4-(4-methylpyrimidin-2-yl)piperazin-1-yl]butan-1-ol and then salifiedwith fumaric acid in ethanol.

M.p.=144° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄OH: 90/9/1,Rf=0.7.

EXAMPLE 35-[4-[4-(4,6-Dimethylpyrimidin-2-yl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate (3)

This compound is prepared according to the process described in Stage fof Example 1 using4-[4-(4,6-dimethylpyrimidin-2-yl)piperazin-1-yllbutan-1-ol (preparedaccording to Process 2a) and THF, and then salified with fumaric acid inethanol.

M.p.=180° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄OH: 90/9/1,Rf=0.61.

EXAMPLE 45-[4-[4-(4-Methoxypyrimnidin-2-yl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate 4)

This compound is prepared according to the process described in Stage fof Example 1 using4-[4-(4-methoxypyrimidin-2-yl)piperazin-1-yl]butan-1-ol (preparedaccording to Process 2a) and THF, and then salified with fumaric acid inethanol.

M.p.=164° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄OH: 90/9/1,Rf=0.6.

EXAMPLE 55-[4-[4-(5-Methoxypyrimidin-2-yl)piperazin-1-yl]butoxyl-2-methyl-2H-[1,2,4]triazin-3-one(5)

This compound is prepared according to the process described in Stage fof Example 1 using4-[4-(5-methoxypyrimidin-2-yl)piperazin-1-yl]butan-1-ol (preparedaccording to Process 2a) and dioxane.

M.P.=101° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.58.

EXAMPLE 65-[4-[4-(4-Chloropyrimidin-2-yl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-one(6)

4-Piperazin-1-yl-butan-1-ol (6a)

Piperazine (50 g, 580 mmol) is placed in 500 ml of acetonitrile and themixture is heated to 60° C. K₂CO₃ (96 g, 694 mmol) is added and thereaction mixture is brought to reflux. 4-Chlorobutanol (58 ml, 581 mmol)is then run in dropwise and then reflux is maintained for 4 h.

After filtering off the inorganic products, the filtrate is concentratedto dryness under vacuum. The residue obtained is purified by silicaflash chromatrography (eluent: CH₂Cl₂/MeOH/NH_(4OH:) 80/18/2) and 51 gof a light-colored oil 6a are recovered.

TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄OH: 80/18/2, Rf=0.40.

b) 4-[4-(4-Chloropyrimidin-2-yl)piperazin-1-yl]butan-1-ol (6b)

The compound 6a (30 g, 189 mmol) and triethylamine (31.6 ml, 226 mmol)are placed in toluene and then the mixture is brought to reflux.2,4-Dichloropyrimidine (28.2 g, 189 mmol) is then added and reflux ismaintained for 3 h.

After concentrating the reaction mixture to dryness, the residue istaken up in H₂O saturated with NaHCO₃ and is extracted withdichloromethane. The organic phases are dried over MgSO₄ and thenconcentrated to dryness. The residue obtained is purified by silicaflash chromatography (eluent: CH₂Cl₂/MeOH: 95/5) and 9.13 g of product6b are recovered in the form of an oil.

TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 95/5, Rf=0.56.

c)5-(4-[4-(4-Chloropyrimidin-2-yl)piperazin-1-yllbutoxy]-2-methyl-2H-[1,2,4]triazin-3-one(6)

This compound is prepared according to the process described in Stage fof Example 1 using4-[4-(4-chloropyrimidin-2-yl)piperazin-1-yl]butan-1-ol 6b and THF.

M.p.=96° C.; TLC, 60 P 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄OH: 90/9/1,Rf=0.6.

EXAMPLE 75-[4-[4-(5-Fluoropyrimidin-2-yl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-one(7)

This compound is prepared according to the process described in Example6 using, in Stage b, 5-fluoro-2-chloropyrimidine.

M.p.=102° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.46.

EXAMPLE 82-Propyl-5-(4-(4-pyrimidin-2-yl-piperazin-1yl)butoxy]-2H-([1,2,4]triazin-3-onefumarate (8)

This compound is prepared according to the process described in Stage fof Example 1 using 4-(4-pyrimidin-2-yl-piperazin-1-yl)butan-1-ol(prepared according to Example 2a) and2-propyl-5-methylsulfanyl-2H-[1,2,4]triazin-3-one (prepared according toExample 1c using propyl iodide) in THF, and then salified with fumaricacid in ethanol.

M.p.=131° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄OH: 90/9/1,Rf=0.55.

EXAMPLE 92,6-Dimethyl-5-(4-(4-pyrimidin-2-yl-piperazin-1-yl)butoxy]-2H-[1,2,4]triazin-3-one(9)

This compound is prepared according to the process described in Example1 using 6-methyl-2H-[1,2,4]triazin-3,5-dione in Stage a and4-(4-pyrimidin-2-yl-piperazin-1-yl)butan-1-ol (prepared according toProcess 2a) and dioxane in Stage f.

M.p.=69° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.47.

EXAMPLE 102-Methyl-6-phenyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butoxy]-2H-[1,2,4]triazin-3-one(10)

This compound is prepared according to the process described in Example1 using 6-phenyl-2H-[1,2,4]triazin-3,5-dione in Stage a and4-(4-pyrimidin-2-yl-piperazin-1-yl)butan-1-ol (prepared according toProcess 2a) and dioxane in Stage f.

M.p.=99° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.48.

EXAMPLE 112-Methyl-6-benzyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butoxyl]-2H-[1,2,4]triazin-3-one(11)

This compound is prepared according to the process described in Example1 using 6-benzyl-2H-[1,2,4]triazin-3,5-dione in Stage a and4-(4-pyrimidin-2-yl-piperazin-1-yl)butan-1-ol (prepared according toProcess 2a) and dioxane in Stage f.

M.p.=86° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.33.

EXAMPLE 122-Benzyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butoxy]-2H-[1,2,4]triazin-3-one(12)

This compound is prepared according to the process described in Example1 using benzyl chloride in Stage c and4-(4-pyrimidin-2-yl-piperazin-1-yl)butan-1-ol (prepared according toProcess 2a) and dioxane in Stage f.

M.p.=86° C.; TLC, 60 F 284 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.38.

EXAMPLE 132-Methyl-5-[3-(4-pyrimidin-2-yl-piperazin-1-yl)propoxy]-2H-[1,2,4]triazin-3-onefumarate (13)

This compound is prepared according to the process described in Example1, Stage f, using 4-(4-pyrimidin-2-yl-piperazin-1-yl)propan-1-ol(prepared according to Process 2a from 3-chloropropanol) and dioxane,and then salified with fumaric acid in methanol.

M.p.=167° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄OH: 90/9/1,Rf=0.60.

EXAMPLE 142-Methyl-5-[5-(4-pyrimidin-2-yl-piperazin-1-yl)pentyloxy]-2H-[1,2,4]triazin-3-one(14)

This compound is prepared according to the process described in Example1, Stage f, using 4-(4-pyrimidin-2-yl-piperazin-1-yl)pentan-1-ol(prepared according to Process 2a from 5-choropentanol) and dioxane.

M.p.=98° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH40H: 90/9/1,Rf=0.50.

EXAMPLE 155-[4-[4-(3-Methoxypyridin-2-yl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate (15)

This compound is prepared according to the process described in Example1, Stage f, using 4-(4-(3-methoxypyridin-2-yl)piperazin-1-yl)butan-1-ol(prepared according to Example 2a) and THF, and then salified withfumaric acid in ethanol.

M.p.=146° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.38.

EXAMPLE 165-[4-[4-(3-Chlorophenyl)piperazin-1-yl]Butoxy]-2-methyl-2H-[1,2,4]Triazin-3-onefumarate (16)

This compound is prepared according to the process described in Example1 in Stage f using 4-(4-(3-chlorophenyl) piperazin-1-yl )butan-1-ol(prepared according to Example 2a) and dioxane, and then salified withfumaric acid in ethanol.

M.P.=153° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90110,Rf=0.47.

EXAMPLE 175-[4-[4-(5-Chloro-2-methoxyphenyl)-piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-one fumarate (17)

This compound is prepared according to the process described in Example1 in Stage f using4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butan-1-ol (preparedaccording to Example 2a) and dioxane, and then salified with fumaricacid in ethanol.

M.p.=184° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.65.

EXAMPLE 184-[4-[4-(2-Methyl-3-oxo-2,3-dihydro-[1,2,4]triazin-5-yloxy)Butyl]piperazin-1-yl]Benzonitrile(18)

This compound is prepared according to the process described in Example1 in Stage f using 4-(4-(4-hydroxybutyl)piperazin-1-yl)benzonitrile(prepared according to Example 2a) and dioxane.

M.p.=132° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.56.

EXAMPLE 195-[4-[4-(5-Chloro-2-methoxyphenyl)-piperazin-1-yl]butoxyl-2-methyl-2H-[1,2,4]triazin-3-onefumarate (19)

This compound is prepared according to the process described in Example1 in Stage f using4-(4-(5-chloro-2-methoxyphenyl)piperazin-1-yl)butan-1-ol (preparedaccording to Example 2a) and dioxane, and then salified with fumaricacid in methanol.

M.p.=149° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.54.

EXAMPLE 205-[4-((2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)amino]butoxyl-2-methyl-2H-[1,2,4]triazin-3-onefumarate (20)

This compound is prepared according to Example 1 usingC-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methylamine in Stage d, and thensalified with fumaric acid in ethanol.

M.p.=152° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄OH: 90/9/1,Rf=0.58.

EXAMPLE 21(R)-5-[4-[(2,3-Dihydrobenzo[1,4)dioxin-2-ylmethyl)amino]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate (21)

a) (R)-Trifluoromethanesulfonic acid -2,3-dihydro)benzo[1,4]dioxin-2-ylmethyl ester (21a)

(R)-(2,3-Dihydrobenzo[1,4]dioxin-2-yl)methanol (3.6 g, 21.7 mmol) isplaced in 320 ml of dichloromethane at −5° C. Triflic anhydride (3.3 ml,19.7 mmol) in 20 ml of CH₂Cl₂ is then run in dropwise. This mixture isstirred for 5 h at −5° C.

The reaction mixture is subsequently washed with 50 ml of 1N HCl andthen with water. The organic phase is dried over MgSO₄ and thenconcentrated to dryness. The oil 21a obtained is used without furtherpurification in the following stage.

b) (R)-4-[(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)amino]butan-1-ol (21b)

The compound 21a is placed in 30 ml of dichloromethane. 4-Aminobutanol(3.6 ml, 38.90 mmol), diluted in 10 ml of CH₂Cl₂, is then run dropwiseinto the reaction mixture. Stirring of the mixture is maintained for 14h at room temperature.

The reaction mixture is concentrated to dryness and the residue is takenup in H₂O. After extracting with CH₂Cl₂, drying the organic phases overMgSO₄ and concentrating to dryness, an oil is isolated. It is purifiedby silica flash chromatography (eluent: CH₂Cl₂/MeOH/NH₄OH: 90/9/1) and2.5 g of light-colored oil 21b are obtained.

TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH4OH: 90/9/1, Rf=0.33.

c)(R)-5-[4-[(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)amino]butoxy)-2-methyl-2H-[1,2,4]triazin-3-onefumarate (21)

The final compound is obtained according to the process described inExample 1, Stage f, using the aminoalcohol 21b and dioxane, and thensalified with fumaric acid in methanol.

M.p.=137° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH40H: 90/9/1,RF=0.65.

EXAMPLE 22(S)-5-[4-[(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)amino]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate (22)

This compound is obtained according to the process described in Example21 using (S)-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methanol.

M.p.=135° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄OH: 90/9/1,Rf=0.59.

EXAMPLE 23trans-2-Methyl-5-(2-pyrimidin-2-yl-octahydropyrido[1,2-a]pyrazin-7-ylmethoxy)-2H-[1,2,4]triazin-3-one(23)

This compound is obtained according to the process described in Example1 in Stage f usingtrans-2-pyrimidin-2-yl-octahydropyrido[1,2a]pyrazin-7-yl)-methanol andpotassium tert-butoxide.

M.p.=140° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.35.

EXAMPLE 24 trans-2-Methyl-5- [2- (2-pyrimidin-2-yl-octahydropyrido 1,2-a]pyrazin-7-yl)ethoxy]-2H-1,2,4ltriazin-3-one (24)

a) 2-Pyrimidin-2-yl-octahydropyrido[1,2-a]pyrazine-7-carbaldehyde (24a)

Oxalyl chloride (6.2 ml, 68.9 imol) is placed in 220 ml ofdichioromethane at −50° C. DMSO (10 ml, 140.9 mmol), diluted in 25 ml ofdichloromethane, is added. trans-(2-Pyrimidin-2-yl-octahydropyrido[1,2a)]-pyrazin-7-yl)methanol, diluted in 30 ml of CH₂Cl₂, is rundropwise onto this mixture maintained at −50° C.

After stirrring for 0.5 h at −50° C., triethylamine (40.8 ml, 293 mmol)is added and the temperature of the reaction mixture is brought back toroom temperature.

The reaction mixture is washed with H₂O and then the organic phase isdried over MgSO₄ and then concentrated to dryness. The oil obtained 24ais purified by flash chromatography, CH₂Cl₂/MeOH: 90/10.

TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄0H: 90/9/1, Rf=0.24.

b) (2-Pyrimidin-2-yl-octahydropyrido[1,2-a]pyrazin-7-yl)acetaldehyde(24b)

Methoxymethyltriphenylphosphonium chloride 41.4 g, 120.8 mmol) anddasopropylamine (11.6 ml, 88.5 mmol) are placed in 180 ml of THF at 0°C. under an inert atmosphere. n-Butyllithium (1.6M solution in THF, 55.2ml, 88.3 mol) is run in dropwise and this mixture is stirred for 1 h atroom temperature. The reaction mixture is brought back to 0° C. and 24a,diluted in 120 ml of THF, is run in dropwise. This mixture is stirredovernight at room temperature and then concentrated to dryness.

The residue is taken up in H₂O and extracted with ethyl acetate. Theorganic phases are washed with acidic H₂O (pH=1). This aqueous phase iswashed with AcOEt, then brought back to pH 12 (concentrated NaOHsolution) and extracted with dichloromethane. These organic phases aredried (MgSO₄) and then concentrated to dryness. The oil obtained ispurified twice by silica flash chromatography (eluent: CH₂Cl₂/MeOH:90/10 and AcOEt/acetone: 50/50). 6.3 g of yellow oil are recovered.

TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄OH: 90/9/1, Rf=0.34.

c) 2-(2-Pyrimidin-2-yl-octahydropyrido[1,2-a]pyrazin-7-yl)ethanol (24c)

NaBH4 (1 g, 10.2 mmol) is placed in 30 ml of ethanol and then 24b (6.3g, 24.2 mmol), diluted in 40 ml of ethanol, is run in dropwise. Thismixture is stirred overnight at room temperature and then hydrolyzedwith water.

After extraction with dichloromethane, the organic phases are dried(MgSO₄) and then concentrated to dryness. The residue obtained ispurified by silica flash chromatography (eluent: CH₂Cl₂/MeOH: 90110).4.5 g of yellow oil are recovered.

TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10, Rf=0.12.

d)trans-2-Methyl-5-[2-(2-pyrimidin-2-yl-octahydropyrido[1,2-a]pyrazin-7-yl)ethoxy]-2H-[1,2,4]triazin-3-one(24)

This compound is obtained according to the process described in Example1 in Stage f using the alcohol 24c and dioxane.

M.p.: 145° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.33.

EXAMPLE 25trans-(−)-2-Methyl-5-[2-(2-pyrimidin-2-yl-octahydropyrido[1,2-a]pyrazin-7-yl)ethoxy]-2H-[1,2,4]triazin-3-one(25)

The racemate prepared according to Example 24 is separated bypreparative HPLC chromatography [silica grafted Chiracel OD-20 μm,eluent: hexane/isopropanol: 65/35 and 1/1000 of diethylamine]. An oil isisolated and again purified by flash chromatography (eluent:CH₂Cl₂/MeOH: 90/10). After crystallizing from an ether/isopropyl ethermixture, 0.31 g of white crystals is isolated.

M.p.=145° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.36.

EXAMPLE 26trans-(+)-2-Methyl-5-12-(2-pyrimidin-2-yl-octahydropyrido[1,2-a)pyrazin-7-yl)ethoxy]-2H-[1,2,4]triazin-3-one(26)

This compound is isolated according to the process described in Example25. 0.42 g of white solid is isolated.

M.p.=146° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.36.

EXAMPLE 272-Methyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butylamino]-2H-[1,2,4]triazin-3-one(27)

a) 4-(4-Pyrimidin-2-yl-piperazin-1-yl)butylamine (27a)

Pyrimidin-2-yl-piperazine dihydrochloride (17.5 g, 73.8 mmol) and4-bromobutylphthalimide (25 g, 88 mmol) are placed in 200 ml ofn-butanol and heated at reflux for 8 h. After concentrating the reactionmixture to dryness, the residue obtained is taken up in 100 ml ofethylenediamine and heated at reflux for 5 h.

The reaction mixture is concentrated under vacuum, the residue is takenup in basic H₂O (pH=11) and this aqueous phase is extracted withdichloromethane. The organic phases are dried over MgSO₄ and thenconcentrated to dryness. The residue obtained is purified by- silicaflash chromatography (CH₂Cl₂/MeOH/NH₄OH: 90/9/1) and 10 g of oil,corresponding to the product 27a, are recovered.

TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH/NH₄OH: 80/18/2, Rf=0.24.

2-Methyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butylamino]-2H-[1,2,4]triazin-3-one(27)

The amine 27a (2.2 g, 9.3 mmol) is placed in 30 ml of toluene in thepresence of 1c (1.7 g, 11.2 mmol) and the mixture is heated at refluxfor 4 h. The reaction mixture is concentrated to dryness under vacuumand the residue is taken up in H₂O/NaHCO₃ and extracted withdichloromethane. The aqueous phases are dried over MgSO₄ and thenconcentrated to dryness. The residue obtained is purified by silicaflash chromatography (eluent: CH₂Cl₂/MeOH: 90/10) and 2.50 g of whitecrystals are obtained.

M.p.=188° C.; TLC, 60 F 254 Merck silica gel; CH₂Cl₂/MeOH: 90/10,Rf=0.26.

The compounds of the invention have been subjected to pharmacologicaltests which have demonstrated their advantage as therapeutically activesubstances.

Binding to the 5-HT_(1A), D₂ dopaminergic and α1-adrenergic receptors:

Brains from male Sprague-Dawley 180-200 g rats [Ico: OFA SD (I.O.P.S.Caw); Iffa Credo, France], maintained at −70° C., were used in all thestudies.

The affinity of the products for the various receptors was determined bydisplacement of radioactive ligands under the conditions summarized inTable 1.

The reaction is halted by rapid filtration, under vacuum, throughWhatman GF/B filters and the tubes are rinsed with 2×5 ml of Tris-HCl 50mM, pH 7.4, buffer at 25° C. The radioactivity collected on the filteris analyzed by liquid scintillation after addition of 4 ml of liquidscintillant (Emulsifier Safe, Packard). All the experiments are carriedout in triplicate.

The inhibition constants (Ki) of the products are estimated from thedisplacement experimentations by using the EBDA (equilibrium bindingdata analysis) Radlig version 4 nonlinear regression program (Biosoft,Cambridge, UK; McPherson, 1985).

The pKi (−log Ki) values are given in the form of the mean ± SEM of atleast 3 experimentations (Table 2).

TABLE 1 Experimental conditions for binding to the receptors Nonspecific[³H] ligand Incubation binding Concen- Tissue Temper- Concen- BindingK_(D) tration Concen- Time ature tration site (nM) (nM) Type tration(min) (° C.) Product (μM) Buffer References 5-HT_(1A) 8-OH- 0.2 cortex10 30 23 5-HT 10 A Assié et al., DPAT mg/ml Eur. J. (3.1) Pharmacol.,304, 15-21, 1996 D₂ YM- 0.05 stria- 1 mg/ml 60 23 (+)- 1 B Assié et al.,09151-2 tum Buta- Eur. J. (0.036) clamol Pharmacol., 237, 183-189, 1993α₁ Prazo- 0.1 cortex 5 mg/ml 30 23 Phento- 50 C Assié and sin lamineKoek, Eur. J. (0.063) Pharmacol., 304, 15-21, 1996 Buffers: (A) Tris HCl50 mM pH 7.4, pargyline 10 μM, CaCl₂ 4 mM, 0.1% ascorbic acid; (B) TrisHCl 50 mM pH 7.4, NaCl 120 mM, KCl 5 mM; (C) Tris HCl 50 mM pH 7.4

TABLE 2 pKi Compound No. 5-HT_(1A) α₁ D₂  1 9.17 6.25 5.80  2 9.57 6.115.76  3 9.56 6.01 5.95  4 9.86 6.74 5.65  6 9.68 6.25 5.77  7 9.04 159.58 16 10.12 17 9.89 19 9.51 8.21 7.82 20 9.97 7.65 7.18 21 9.48 2210.47 24 9.28 6.35 5.54 26 9.61 Buspirone 7.65 6.19 7.49 Flesinoxan 8.916.50 7.05

Serotoninergic Syndrome:

The central activity of the compounds of the invention was evaluated bytheir ability to provoke the 5-HT syndrome, which is characterized by:

an alternating bending and stretching of the forepaws (reciprocalfore-paw treading: FPT)

the retraction of the lower lip (lower lip on: LLR)

a position or the ventral surface of the animal is incobtact with theground and the hind paws extended (flat body posture: FBP).

The experiments on the evaluation of the 5-HT syndrome are carried outwith the male rat (Sprague-Dawley) according to the technique describedby F. C. Colpaert et al. (Drug. Dev. Res, 26, 21-48, 1992) and M. S.Kleven et al. (J.P.E.T., 282, 747-759, 1997).

The active doses (ED₅₀) for some derivatives of the invention, incomparison with reference products such as Buspirone and Flesinoxan, aregiven in Table 3 by way of example.

TABLE 3 5-HT syndrome ED₅₀ mg/kg po Compound No. FBP LLR FPT  1 0.080.02 0.08  2 0.08 0.02 0.08  3 0.08 0.08 0.08  4 0.08 <0.04 0.08  6 0.080.08 0.08  7 0.31 0.08 0.31 17 0.31 0.08 0.31 20 0.08 <0.04 0.31 24 0.08<0.04 0.08 26 <0.04 <0.04 0.04 Buspirone 20 2.5 >40 Flesinoxan 1.25 1.255

Antidepressant Activity: Forced Swimming Test:

The compounds of the invention are tested according to the proceduredescribed by R. Porsolt et al. (Eur. J. Pharmacol., 47, 379-391, 1978).

The active doses (ED₅₀) are calculated for each compound according tothe percentages of animals exhibiting a significant decrease, incomparison with the control animals (p<0.05), in the immobility time(Table 4).

TABLE 4 Compound No. ED₅₀ mg/kg po  2 0.04  6 0.63 24 0.04 26 0.04Buspirone >160 Flesinoxan 1.25

The results of the various tests show that the compounds of generalformula I possess, in vitro, a high affinity for the serotoninergicreceptors of 5-HT_(1A) type and good selectivity with regard to α₁ andD₂ receptors. They show, in vivo, an agonist activity with regard to5-HT_(1A) receptors and are powerfully active with regard to behavioralmodels, such as the forced swimming test.

The compounds of the invention can therefore be of use in the treatmentof anxiety, depression, pain, neurodegeneration, schizophrenia,Alzheimer's disease and sleep disorders, for the regulation of foodintake, for the regulation of gastric secretion and for the treatment ofvascular, cardiovascular and cerebrovascular disorders, such ashypertension or migraine.

The pharmaceutical preparations comprising compounds of general formulaI as active principlg can be formulated for oral, rectal or parenteraladministration, for example in the form of capsules, including hardgelatin capsules, tablets, granules, liquid solutions, syrups orsuspensions to be taken orally, and can comprise the appropriateexcipients.

It is also possible to combine therein other pharmaceutically andtherapeutically acceptable active principles.

What is claimed is:
 1. A 3-oxo-(2H)-1,2,4-triazine derivative selectedfrom those of formula I

in which r₁ represents: a linear or branched C₁-C₄ alkyl group or aphenyalkyl group, the phenyl nucleus optionally being substituted by oneor more C₁-C₄ alkyl, C₁-C₃, alkoxy, halogen, and trifluoromethyl, R₂represents; hydrogen or a linear or branched C₁-C₄ alkyl radical or aphenyl or phenyalkyl group, the phenyl nucleus optionally beingsubstitued by one or more C₁-C₄ alkyl, C₁-C₃ alkoxy, halogen, andtrifluoromethyl, A represents oxygen, R₃ represents hydrogen or methyl,B represents a group

 in which Ar represents phenyl, pyridyl, or pyrimidyl, optionallysubstituted by one or more C₁-C₃ alkyl, C₁-C₃ alkoxy, hydroxyl,trifluoromethyl, and halogen, and n is 3 to5,  in the form of a racemicmixture or an enantiomer or diastereoisomer thereof andpharmaceutically-acceptable inorganic or organic salts thereof.
 2. Acompound according to claim 1, chosen from the following compounds:2-Methyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butoxy]-2H-[1,2,4]triazin-3-one2-Methyl-5-[4-[4-(4-methylpyrimidin-2-yl)piperazin-1-yl]butoxy]-2H-[1,2,4]triazin-3-onefumarate5-[4-[4-(4,6-Dimethylpyrimidin-2-yl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate5-[4-[4-(4-Methoxypyrimidin-2-yl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate5-[4-(4-(5-Methoxypyrimidin-2-yl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-one5-14-[4-(4-Chloropyrimidin-2-yl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-one5-[4-[4-(5-Fluoropyrimidin-2-yl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-one2-Propyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butoxy]-2H-[1,2,4]triazin-3-onefumarate2,6-Dimethyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butoxy]-2H-[1,2,4]triazin-3-one2-Methyl-6-phenyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butoxy]-2H-[1,2,4]triazin-3-one2-Methyl-6-benzyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butoxy]-2H-[1,2,4]triazin-3-one2-Benzyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butoxy]-2H-[1,2,4]triazin-3-one2-Methyl-5-[3-(4-pyrimidin-2-yl-piperazin-1-yl)propoxy]-2H-[1,2,4]triazin-3-onefumarate 2-Methyl-5-[5-(4-pyrimidin-2-yl-piperazin-1-yl)pentyloxy]-2H-[1,2,4]triazin-3-one5-[4-[4-(3-Methoxypyridin-2-yl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate5-[4-[4-(3-Chlorophenyl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate5-[4-[4-(5-Chloro-2-methoxyphenyl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate4-[4-[4-(2-Methyl-3-oxo-2,3-dihydro-[1,2,4]triazin-5-yloxy)butyl]piperazin-1-yl]benzonitrile5-[4-[4-(5-Chloro-2-methoxyphenyl)piperazin-1-yl]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate5-[4-[(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)amino]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate(R)-5-[4-[(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)amino]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumarate(S)-5-[4-[(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethyl)amino]butoxy]-2-methyl-2H-[1,2,4]triazin-3-onefumaratetrans-2-Methyl-5-(2-pyrimidin-2-yl-octahydropyrido[,2-a]pyrazin-7-ylmethoxy)-2H-[1,2,4]triazin-3-onetrans-(−)-2-Methyl-5-[2-(2-pyrimidin-2-yl-octahydropyrido[1,2-a]pyrazin-7-yl)ethoxy]-2H-[1,2,4]triazin-3-onetrans-(+)-2-Methyl-5-[2-(2-pyrimidin-2-yl-octahydropyrido[1,2-a]pyrazin-7-yl)ethoxy]-2H-[1,2,4]triazin-3-one;and2-Methyl-5-[4-(4-pyrimidin-2-yl-piperazin-1-yl)butylamino]-2H-[1,2,4]triazin-3-one.3. Process for the preparation of the a compound according to claim 1wherein a compound of formula III

is treated with an alcohol B-OH IV R₁, R₂, R₃ and B being as defined inclaim 1, in the presence of sodium hydride or of potassium tertbutoxidein dioxane, tetrahydrofuran or toluene.
 4. Pharmaceutical composition,comprising, as active principle, a compound according to claim 1 incombination with a pharmaceutically acceptable excipient. 5.Pharmaceutical composition comprising a compound according to claim 2 incombination with a pharmaceutically-acceptable excipient.
 6. Method oftreating a living animal suffering from a disease requiring an agonistof 5-HT1A receptors wherein said disease is selected from anxiety,depression, schizophrenia, consisting of the step of administering tosaid animal an amount of a compound of claim 1 which is effective foramelioration of said disease.
 7. Method of treating a living animalsuffering from a disease requiring an agonist of 5-HT1A receptorswherein said disease is selected from anxiety, depression,schizophrenia, consisting of the step of administering to said animal anamount of a compound of claim 2 which is effective for amelioration ofsaid disease.